TY - JOUR
T1 - Aβ peptides can enter the brain through a defective blood-brain barrier and bind selectively to neurons
AU - Clifford, Peter M.
AU - Zarrabi, Shabnam
AU - Siu, Gilbert
AU - Kinsler, Kristin J.
AU - Kosciuk, Mary C.
AU - Venkataraman, Venkateswar
AU - D'Andrea, Michael R.
AU - Dinsmore, Steven
AU - Nagele, Robert G.
N1 - Funding Information:
The authors wish to acknowledge the generous support of the National Institute on Aging (AG00925), Alzheimer's Association, the New Jersey Governor's Council on Autism and the New Jersey Gerontological Institute. Some tissue samples were provided by the Cooperative Human Tissue Network which is funded by the National Cancer Institute.
PY - 2007/4/20
Y1 - 2007/4/20
N2 - We have investigated the possibility that soluble, blood-borne amyloid beta (Aβ) peptides can cross a defective blood-brain barrier (BBB) and interact with neurons in the brain. Immunohistochemical analyses revealed extravasated plasma components, including Aβ42 in 19 of 21 AD brains, but in only 3 of 13 age-matched control brains, suggesting that a defective BBB is common in AD. To more directly test whether blood-borne Aβ peptides can cross a defective BBB, we tracked the fate of fluorescein isothiocyanate (FITC)-labeled Aβ42 and Aβ40 introduced via tail vein injection into mice with a BBB rendered permeable by treatment with pertussis toxin. Both Aβ40 and Aβ42 readily crossed the permeabilized BBB and bound selectively to certain neuronal subtypes, but not glial cells. By 48 h post-injection, Aβ42-positive neurons were widespread in the brain. In the cerebral cortex, small fluorescent, Aβ42-positive granules were found in the perinuclear cytoplasm of pyramidal neurons, suggesting that these cells can internalize exogenous Aβ42. An intact BBB (saline-injected controls) blocked entry of blood-borne Aβ peptides into the brain. The neuronal subtype selectivity of Aβ42 and Aβ40 was most evident in mouse brains subjected to direct intracranial stereotaxic injection into the hippocampal region, thereby bypassing the BBB. Aβ40 was found to preferentially bind to a distinct subset of neurons positioned at the inner face of the dentate gyrus, whereas Aβ42 bound selectively to the population of large neurons in the hilus region of the dentate gyrus. Our results suggest that the blood may serve as a major, chronic source of soluble, exogenous Aβ peptides that can bind selectively to certain subtypes of neurons and accumulate within these cells.
AB - We have investigated the possibility that soluble, blood-borne amyloid beta (Aβ) peptides can cross a defective blood-brain barrier (BBB) and interact with neurons in the brain. Immunohistochemical analyses revealed extravasated plasma components, including Aβ42 in 19 of 21 AD brains, but in only 3 of 13 age-matched control brains, suggesting that a defective BBB is common in AD. To more directly test whether blood-borne Aβ peptides can cross a defective BBB, we tracked the fate of fluorescein isothiocyanate (FITC)-labeled Aβ42 and Aβ40 introduced via tail vein injection into mice with a BBB rendered permeable by treatment with pertussis toxin. Both Aβ40 and Aβ42 readily crossed the permeabilized BBB and bound selectively to certain neuronal subtypes, but not glial cells. By 48 h post-injection, Aβ42-positive neurons were widespread in the brain. In the cerebral cortex, small fluorescent, Aβ42-positive granules were found in the perinuclear cytoplasm of pyramidal neurons, suggesting that these cells can internalize exogenous Aβ42. An intact BBB (saline-injected controls) blocked entry of blood-borne Aβ peptides into the brain. The neuronal subtype selectivity of Aβ42 and Aβ40 was most evident in mouse brains subjected to direct intracranial stereotaxic injection into the hippocampal region, thereby bypassing the BBB. Aβ40 was found to preferentially bind to a distinct subset of neurons positioned at the inner face of the dentate gyrus, whereas Aβ42 bound selectively to the population of large neurons in the hilus region of the dentate gyrus. Our results suggest that the blood may serve as a major, chronic source of soluble, exogenous Aβ peptides that can bind selectively to certain subtypes of neurons and accumulate within these cells.
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U2 - 10.1016/j.brainres.2007.01.070
DO - 10.1016/j.brainres.2007.01.070
M3 - Article
C2 - 17306234
AN - SCOPUS:33947164189
SN - 0006-8993
VL - 1142
SP - 223
EP - 236
JO - Brain Research
JF - Brain Research
IS - 1
ER -